Gastroenterology

Gastroenterology

Volume 126, Issue 7, June 2004, Pages 1759-1770
Gastroenterology

Basic-alimentary tract
Colitis is associated with thymic destruction attenuating CD4+25+ regulatory T cells in the periphery

https://doi.org/10.1053/j.gastro.2004.03.015Get rights and content

Abstract

Background & Aims: Syngeneic bone marrow transplantation into the adult tgε26 mouse results in severe wasting disease and colitis. On transplantation, the rudimentary thymus of the adult tgε26 mouse repopulates briefly but quickly regresses in temporal association with the onset of colitis. The aim of this study is to test the hypothesis that treatment of colitis restores thymic capability to generate regulatory T cells (CD4+25+ TR cells). Methods: Colitis was induced by bone marrow transplantation into adult irradiated tgε26 mice. Colitis was prevented by 3 distinct modalities. CD4+25+ T cells were collected from both the thymus and spleen and studied for regulatory function by an in vitro suppression assay. Results: CD4+25+ TR cells do not develop efficiently in the thymus of bone marrow transplanted adult tgε26 mice, which have a developmental arrest affecting thymic epithelium. By contrast, the thymic epithelium of neonatal tgε26 mice supports development of TR cells. Consequently, colitis develops only in adult transplanted mice but not in the neonatally transplanted mice. Treatment of colitis prevents destruction of the thymus of adult transplanted tgε26 mice and TR cells are produced. Conclusions: The negative impact of colitis on TR development in the thymus, which was confirmed in a second model of colitis, has profound implications for the pathogenesis and treatment of human inflammatory bowel disease.

Section snippets

Mice

The tgε26 recipient mice, derived from (C57BL/6 × CBA) F1 (H2Kk/b) mice, were maintained as previously described.10 (C57BL/6 × CBA) F1 mice were purchased from Jackson Laboratory (Bar Harbor, ME). C57BL/6 TCR transgenic HY-Rag−/− mice were purchased from Taconic Laboratory (Germantown, NY). For all experiments involving HY-Rag−/− mice, only female mice were used. C57BL/6 TCR transgenic F5-RAG−/− (F5) mice were generously provided by Dr. C. Levelt (MIT, Cambridge, MA).11 Signal transducer and

TR cells develop in bone marrow transplanted neonatal tgε26 mice

To examine whether a temporal window existed, during which wt hematopoietic cells did reconstitute the tgε26 thymus, 2- to 8-day-old tgε26 neonates were transplanted with bone marrow from wt (C57BL/6 × CBA) F1 mice. The resultant BM→tgε26neo mice developed a thymus that had a normal distribution of CD4, CD8, TCR-αβ, and CD3 positive cells (Table 1). In the spleen and lymph nodes of the mice, mature T cells were detected at levels 70% to 100% of wt controls in the peripheral lymphoid organs (

Discussion

This study shows that when a neonatal tgε26 mouse receives BM, TR cells develop, protecting the mouse from colitis. Conversely, in BM→tgε26adult mice, few TR cells can be detected. The neonatal tgε26 thymus is therefore similar to the Rag−/− thymus in that both support development of TR cells. Unlike the Rag−/− thymus, the adult tgε26 thymus lacks keratin 8+5 cortical thymic epithelial cells (TECs).7, 18 High-affinity interaction between developing thymocytes and MHC class II expressing

Acknowledgements

The authors thank Dr. D. Podolsky, D. Howie, and M. Morra for a critical review of the manuscript and M. Comiskey for technical support.

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  • Cited by (0)

    Supported by grants from the National Institutes of Health (DK52510 to C.T.; DK47677 to A.K.B.; DK43351 to C.T. and A.K.B.) and the Crohn’s and Colitis Foundation of America (to Y.P.D. and S.J.S.).

    1

    W.A.F. and Y.P.D. contributed equally to this paper.

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